Pulmonary fungal infections, which are associated with significant levels of morbidity and mortality, represent a major medical challenge. In recent years, the frequency and seriousness of fungal infections has increased, due to increasing numbers of organ transplantations, aggressive antineoplastic therapy regimens, and patients suffering from immune diseases such as HIV. Fungal infections of the lung, e.g., fungal pneumonia, allergic bronchopulmonary aspergillosis and other infections caused by Aspergillus, are typically treated by direct intracavitary instillation, oral, intraperitoneal, or intrapleural administration, or intravenous infusion of one or more antifungal agents such as amphotericin B (St. Georgiev, V., Respiration, 59:291-302 (1992). Unfortunately, serious drawbacks exist with each of these commonly employed routes of administration as described more fully below.
Direct intracavitary instillation, an invasive procedure, is usually accomplished by repeated transthoracic injections into the cavity. Drawbacks of intracavitary administration can include poor tolerance (the development of fever), risk of pheumothorax, and relapse of infection in the cavity (Glimp, RA, et al., Arch Intern Med, 143:303-308 (1983). In general, endobronchial administration of antifungals has met with minimal success (Henderson, AH, et al., Thorax, 23:519-523 (1968)). Oral formulations tend to be absorbed very poorly from the gastrointestinal tract, and like intravenous therapy are limited by associated dose-dependent drug toxicity, which (i) limits the intravenous dose that can be administered, and (ii) can result in unpleasant or even life threatening complications such as nephrotoxicity and normochromic anemia. Some of the disadvantages of intravenous therapy using conventional antifungal formulations have been addressed by the development of liposomal compositions such as ambisome (a liposomal formulation of amphotericin B), which, when administered by injection, does not display serious toxicity such as renal tubular damage, and allows the administration of doses which exceed those used in conventional formulations (Hay, R J in Recent Progress in Antifungal Chemotherapy. New York, Marcel Dekker, 1992 (323-332)).
Oral or intravenously administered systemic antifungals for treating respiratory infections suffer from an added disadvantage—the uncertainty of drug penetration into the lung tissue and infected secretions. This is important since effective drug therapy for lower respiratory tract infections depends upon not only the susceptibility of the infecting microorganisms, but upon the attainment of effective antifungal concentrations in the lung tissue and mucus. In an attempt to address this problem, inhalation therapy using nebulizer-generated aerosols has been investigated, using antifungals such as amphotericin B (Beyer, J., et al., Infection, 22:2, 143 (1994); Calvo, V., et al., Chest, 115:5 (1999); Dubois J., et al., Chest, 108:3, 750-753 (1995); Diot, P. et al., Eur Respir J., 8:1263-1268 (1995)).
Aerosolized pharmaceutics for inhalation can be delivered in a variety of different forms, including nebulized sprays, pressurized powder formulations, and non-pressurized powder formulations. Several drawbacks exist for both liquid and pressurized formulations. Disadvantages of liquid formulations include the chemical instability of certain active agents in solution (polyenes in particular), the high potential for microorganism contamination, and the use of cumbersome liquid nebulizers. Pressurized powder formulations containing a compressed gas or liquefied gas propellant have the disadvantages of employing ozone depleting agents in the case of CFCs, or green house gases in the case of HFCs. Further, liquid gas propellant typically cannot accommodate the quantities of antifungal agent required to achieve high levels of fungistatic/fungicidal activity locally at the site of infection. Pressurized powder formulations can also exhibit a high level of variability in the dose that is delivered to the lungs, due the inability of patients to consistently coordinate the firing of the inhaler to generate the aerosol with the appropriate cycling of the inhalation. Achieving adequate solubilization or suspension of antifungal agents such as the polyene, amphotericin B, in the liquefied gas propellant can also be problematic.
Thus, in view of the problems noted above using conventional antifungal therapies, it would be desirable to provide an inhaleable, non-pressurized antifungal dry powder for localized delivery to the lung, for both the treatment of pulmonary fungal infections and for therapy of systemic fungous diseases. Inhaleable dry powder formulations can provide high concentrations of antifungal agent in the lung with negligible concentrations in the blood and body tissues. Moreover, by utilizing a topical administration route, most of the toxicities that are associated with systemic antifungal agents (including nephrotoxicity, convulsions, fever, and chills, among others) can be minimized or avoided. Inhalation of antifungals using a dry powder inhaler maximizes the convenience and speed of administration, and overcomes the disadvantages of alternative inhalation therapies as described above.
Unfortunately, the development of chemically stable dry powders of an antifungal agent such as amphotericin B that also possess the physical properties necessary for aerosolization (e.g., high dispersibilities which remain stable over time, appropriate aerodynamic size) remains a technical challenge.